. The primary goal of this proposal is to explore the hypothesis that the Notch pathway plays an important role in the development of chronic kidney disease and kidney fibrosis. We found via large scale genome screening that Notch pathway proteins are regulated in patients and animal models chronic kidney disease and fibrosis. In this application we propose to perform a systematic analysis to examine the role of renal tubular epithelial Notch signaling in the adult kidney at baseline and diseased kidneys. First we will examine whether tubular epithelial Notch signaling plays any role in the adult kidney homeostasis, aging and repair. Next we will analyze which Notch receptor and ligand isoforms is responsible for the renal damage during injury. The third specific aim will define the molecular mechanism of Notch induced epithelial dysfunction and interstitial fibrosis. The current proposal will built on our original observation and explore the role of Notch signaling in the adult kidney both at baseline and in injury models. These studies will help not only deepen our understanding of renal epithelial homeostasis, but also aid the potential development of Notch based inhibitors for chronic kidney disease. PUBLIC HEALTH RELEVANCE: Approximately 20 million people in the US suffer from chronic kidney disease (CKD). CKD is associated with an approximately 5-fold increase in cardiovascular mortality. The prevalence of patients with end-stage renal disease (ESRD) reaches more than half a million people in the U.S. alone, and increases at a rate of 5-6% worldwide. The 5-year survival of patients who reaches ESRD is around 20%, which is worse than many different solid tumors. These data highlight the importance and urgency of the current problem in the medical community on a global scale. On phenotypic and histological levels, chronic kidney disease development follows a very similar path. Fibrosis of the kidney is the final common pathway leading to ESRD. Our studies aim to understand the molecular mechanism of kidney fibrosis.